1. Field of Invention
Antihyperlipidemic pharmaceutical or dietary supplement compositions and method of treating hyperlipidemic conditions therewith; combination compositions and therapy employing niacin and another active antihyperlipidemic principle, namely, gel-forming dietary fiber, which eliminate the usual undesirable side effects of niacin.
2. Background of the Invention and Prior Art
Nicotinic acid was the only agent studied by the Coronary Drug Project which produced a significant decrease in coronary events. Coronary Drug Project Research Group: Clofibrate and Niacin and Coronary Heart Disease. JAMA 231:360 (1975). This research demonstrated that niacin lowers blood cholesterol on an average by nine percent and reduces the recurrence rate of myocardial infarction by 29%. The study involved more than 8,000 individuals and was conducted over a period of six (6) years. The usual dosage range for niacin therapy is 3 to 6 grams per day, which dosage is capable of lowering cholesterol level from 10 to 25%, triglyceride level by 45 to 50%, and elevating HDL cholesterol by 15 to 20%.
In a paper in the Journal of Lipid Research 22:24-36 (1981) entitled "Influence of Nicotinic Acid on Metabolis of Cholesterol and Triglycerides in Man", it is stated as follows:
"Although the magnitude of plasma lipid lowering by nicotinic acid can be appreciable, its usefulness has been limited by certain disagreeable side effects such as flushing of the face and other skin reactions." PA1 "Its use has been clinically stymied, however, by side effects.",
Although the actual mechanisms by which niacin reduces cholesterol and triglycerides is not completely known, it is known that niacin does produce these effects and that niacin, moreover, has an ability to increase the amount of the protective form of cholesterol, namely, HDL cholesterol.
A major shortcoming of niacin is the necessity of administering large doses of niacin to effectively lower cholesterol level. Most subjects treated will experience accompanying side effects of flushing, prickling of the skin, and itching when they begin niacin, when the dosage is increased, or when the treatment is temporarily terminated and then commenced once more at the same dose. Ordinarily, it is necessary for a subject to gradually increase the dosage of niacin to a three to six gram per day dosage level over a period of months, starting with one 50 mg tablet three times daily for a total dose of 150 mg per day, to avoid being overwhelmed with the unpleasant side effects.
The prior art is replete with reports of the reduction of cholesterol levels and control of cholesterol levels in a subject in need of the same employing niacin (nicotinic acid) and of the undesirable side effects ordinarily produced when an effective amount of niacin is employed for such purpose. The side effects include flushing and itching, and it is well documented in the literature that such flushing, itching, and so on is not eliminated by intermittent niacin therapy, and generally reappears even when the therapy is interrupted and reinstituted. Although the degree or intensity of such side effects varies from patient to patient, it is frequently observed that such therapy cannot be applied in the case of various patients who are hypersensitive to the niacin or to the side effects which result in such patients upon oral administration thereof.
The present status of niacin treatment has been capsulated by Luria in Arch Intern Med 148, pp. 2493-2495 (Nov 1988) in the following words:
so that only low dosages may be administered with safety and patient acceptability, although even this latter is not a certainty even with low dosages over an extended perod.
Numerous other approaches to the lowering of cholesterol in a subject in need thereof have been proposed. For example, cholestyramine and other drugs which theoretically affect the bile acid pool and pull cholesterol out of the bloodstream according to the postulated mechanism are also available as are the gel-forming dietary fiber materials, such as guar gum and the like. Guar gum has been suggested as a dietary supplement fiber having an effect on cholesterol upon ingestion, but having a somewhat reduced effect when compared to bile acid-binding agents such as cholestyramine. Although the effect of guar gum is clear, its mechanism of action as a plasma cholesterol-lowering agent is unclear. What is clear, however, is that guar gum has no specific affinity for either cholesterol or for bile salts and that it does not act as a bile acid-binding agent in the manner of cholestyramine or the like, being 60-70 percent less effective in this regard, but yet being able to lower cholesterol levels almost as well as cholestyramine.
Dietary supplements or regimens combining oat bran (e.g., 100 grams per patient per day) and niacin have been recommended, but there has been no evidence or suggestion that such combination dietary treatment or approach has any effect upon the undesirable side effects of niacin, least of all at cholesterol-lowering dosages or intakes. Although it has been reported that side effects and especially gastric irritation may be somewhat reduced by taking the medication with meals and by the use of antacids or by combined therapy with colestipol, a bile acid-sequestering resin having proton-binding properties, its side effects continue to hamper its general applicability in cholesterol lowering and poor patient compliance often results because of these side effects.
It is accordingly reported that "Continuous flushing, resulting from harmless dilation of skin capillaries, occurs in most individuals at onset of treatment and when dosage is increased.--Patients should be warned that if several doses are missed, the flushing will recur.--Gastric irritation is also frequently encountered.--"
Since niacin, at a dosage level of three to six grams per day, is very effective in reduction of undesirable cholesterol levels, which reportedly fall by a mean of approximately 22% during some controlled clinical evaluations, it would be highly desirable to provide a way in which this valuable cholesterol-lowering material could be more generally applied without fear of or limitation by the said undesirable side effects, and the present invention addresses this problem, which has heretofore had no satisfactory solution, by combined therapy employing also guar gum, or another gel-forming natural dietary fiber which itself is a dietary supplement and which itself may be known to produce a cholesterol-lowering effect, but which unpredictably, as found according to the present invention, essentially eliminates or at least very substantially reduces the usual niacin side effects when administered simultaneously and preferably in a combination composition therewith.
Combination therapy employing colestipol, a bile acid sequestrant, together with niacin or its prodrug clofibrate, produced reduction in cholesterol levels as expected, which were greater when niacin was used together with colestipol rather than its prodrug clofibrate, but care still had to be taken to "mitigate the prostaglandin-mediated cutaneous flushing often associated with niacin", aspirin therefore being administered a half hour before each dose of niacin for this purpose. Combination therapy involving Lovastatin, plus a resin such as cholestyramine or colestipol, and niacin has also been suggested, it being reported that the Lovastatin reduced the amount of resin and niacin required to produce satisfactory results, and providing a possible powerful therapy for severe familial hypercholesterolemia, although such bile acid-sequestering resins are suspect as possibly binding and at least partially inactivating niacin as well. In any case, the combination of niacin plus the already-established guar gum or other gel-forming dietary fiber supplement (fiber intake already having been established as "inversely related to all-cause mortality"), as provided by the present invention, would appear to be a much simpler solution to the problem of the undesirable niacin side effects, while at the same time providing effective double-barrel cholesterol-lowering effect and results, than any combination, method-of-treating, or dietary supplement approach which has been suggested previously.
Guar gum is derived from a leguminous plant which bears bean-like pods containing six to nine seeds, known as Cyanopsis tetragonoloba. The seed is 40-46% germ, 38-45% endosperm, and 14-16% husk. Guar gum is prepared by first removing the husk and sperm components and then is derived essentially from the endosperm. It is marketed commercially in different grades and is chemically a galactomannan with galactose on every other mannose unit, having a molecular weight of approximately 220,000. It disperses in cold water to form a viscous pseudoplastic sol, the viscosity of which can be enhanced with heating, and it has an extremely high viscosity, which is fivefold higher per unit weight than starch, and is commercially available in various grades of dispersibility, viscosity, and thickening power, being generally packaged in powder form which requires dispersion in water. The problem of dispersing the guar gum in water is one which confronts one desiring to prepare a drinkable dispersion thereof, and also one who desires to disperse the guar gum internally upon oral ingestion, especially when most rapid action is desired. Although the mechanism of action as a plasma cholesterol-lowering agent of guar gum is unclear, it is clear that both niacin (nicotinic acid) and guar gum have been known to be effective cholesterol-lowering entities for at least twenty (20) years but, up to the time of this invention, no one has disclosed or even suggested that a combination of guar gum or any other gel-forming dietary fiber with niacin would virtually eliminate the unpleasant and normally limiting side effects of niacin in addition to providing enhanced cholesterol-lowering effect.
A Dialog search from the U.S. Patents data base for niacin for U.S. Patent Abstracts 1971-81, 1982-1987, and weekly from 12/87 through the middle of February 1988, turned up a few niacin prodrugs with or without allegedly reduced side effects and U.S. Pat. No. 4,166,902 relating to high polymers containing nicotinic acid in which nicotinic acid radicals are bound through covalent ester bonds which gradually hydrolyze in a biological environment by setting free nicotinic acid, and which allegedly have a therapeutic activity similar to that of nicotinic acid itself but longer lasting and with the elimination or least reduction of "collateral effects", the product of this patent apparently being some sort of a "depo" nicotinic acid-containing material, but of course the question remains whether the slow release of nicotinic acid as disclosed in this patent will provide adequate niacin levels for effective cholesterol lowering in practice. At any rate, this patent merely emphasizes the continued existence of the problem of niacin side effects and allegedly provides one approach to its possible solution, being in no way suggestive of the entirely different solution to the problem discovered by the present applicant.
For purposes of definition in this specification, the term "dietary fiber" is defined as "remnants of plant cells resistant to hydrolysis by the alimentary enzymes of man, the group of substances that remain in the ileum but are partly hydrolyzed by bacteria in the colon", according to JAMA 262, pp. 542-546 No. 4 (July 28, 1989) Council Report entitled "Dietary Fiber and Health", at page 542. This article, moreover, gives considerable information as to what constitutes a "dietary fiber" and is accordingly incorporated herein by reference.
Gel-forming dietary fibers include mucillages, plant gums, pectins or pectic substances, and lignin, all of which are endogenous compounds of plant materials which are resistant to digestion by enzymes in the monogastric stomach or small intestine. Chemically, nearly all of these plant materials are carbohydrates composed of repeating monosaccharide (sugar) units. Disaccharides have two sugar units, oligosaccharides three to twelve, and polysaccharides may contain a million or more. The water-soluble fractions of these substances form gels in the stomach and intestinal tract and lower serum cholesterol.
Gums and mucillages have no common structure but are polysaccharides containing several sugars with alternating monomer structures, and may or may not contain uronic acids. There are many gums found in plants and cereal grains. Guar and locust bean gums are galactomannans, whereas gum arabic is an acidic polymer of galactose and rhammose. Oat and barley contain gums, but are not practical for use in the present application because of the low percentage of active gums per weight volume. Large amounts of oat bran (e.g., 100 grams per day) are also required to lower serum cholesterol. Most of the gums in the present application are effective at much lower dosages. Suitable gums include, inter alia, besides guar gum, the following: locust bean gum, acacia gum, gum arabic, xanthan gum, carrageenan gum, karaya gum, tragacanth gum, and ghatti gum.
Pectin substances or pectins are mixtures of polysaccharides of partially methylated and 1,4-D galacturonic acid units with side chains containing arabinose, galactose, xylose, and rhammose. They are contained in many fruits and vegetables as well as other plants.
Other suitable gel-forming dietary fibers include psyllium husks, algal polysaccharides, glucomannan, and agar, to name a few. Lignin is a non-carbohydrate polymer of aromatic plant alcohols comprising oxygenated phenylpropane units. As a plant matures, more lignin is produced, which acts as a sort of cement as it hardens and holds together other plant cell wall constituents. Lignin passes through the digestive tract with very little change.
As already mentioned, a recent review of dietary fiber which mentions these substances is contained in the following reference: Dietary Fiber and Health, JAMA 262: 542-546 (1989), from the Council on Scientific Affairs, American Medical Association.